The goals of this research are: (1)\to understand further the evolution of cell populations in human lung cancers, with particular emphasis on cells with neuroendocrine differentiation features; (2)\to develop new probes for identifying the sequence of differentiation events underlying populations of cells in human lung cancers, again with emphasis on neuroendocrine cells; and (3)\to use the above probes to enhance the accuracy of diagnosis in patients with lung cancer and, potentially, for improved methods of management. During the past 3 years, our laboratory has concentrated on the question of whether the cell surface protein phenotype identified on human lung cancer cells would help define the populations of cells that evolve in human lung neoplasms. Using cell lines established in our own laboratory and lines of human lung cancer from the National Cancer Institute, we have established that a separate pattern of surface proteins distinguishes multiple lines of human small cell lung cancer from the non-small cell lung cancers (adenocarcinomas and squamous cell carcinomas). Most recently, we have shown that large cell undifferentiated cancers that arise via a transition process from small cell carcinomas (both in the host and in cell culture) retain most of the small cell surface proteins, thus helping to identify their lineage. Furthermore, a line of large cell undifferentiated carcinoma of small cell lineage that on a clonal basis manifests cell surface proteins typical for both small cell and non-small cell lung carcinomas has been identified. These data have helped further define that small cell carcinomas and the normal lung endocrine cells probably arise within the same cell lineage as the non-small cell lung carcinomas. Our current emphasis is upon developing specific antibodies to selected small cell and non-small cell surface proteins. (2)